The goal of this research is to develop and test new strategems and methodologies for the synthesis of naturally occurring macrolide antibiotics. Synthetic pathways to five macrolides will be investigated, each of which seeks to elaborate, in a stereo- controlled fashion, the complete molecular architecture of these complex structures. The planned route to avermectin B1a, a broad-spectrum anthelmintic with promising indications for treatment of human parasitic infections, makes use of an intramolecular Julia olefin synthesis for closing the macrocycle. Novel methodology, including translactonization of an interesting bridged gamma-lactone intermediate, is employed for linking the three subunits of avermectin aglycone. Latrunculin A, a potent fish toxin isolated from a marine sponge and possessing activity similar to but more specific than cytochalasin D, is to be assembled from three subunits and a final lactonization-ketalization protocol. The preparation of a key subunit of latrunculin A involves a tandem dianion-Wittig reaction that produces the Z,E-diene moiety stereo- specifically. Synthesis of another marine macrolide, geodiamolide A, possessing antifungal activity, is projected from a novel tripeptide containing m-iodo-N-methyl-D-tyrosine and a nonenoic acid segment. Formation of the depsipeptide is envisioned by means of an Eschenmoser-Claisen rearrangement. Synthesis of cathedulin K-19, a constituent of the natural stimulant and narcotic "khat", necessitates synthesis of its principal structural subunit euonyminol, with subsequent connection of cathic acid and a second dicarboxylic acid to complete the bis macrodiolide. A route to euonyminol based on a Diels-Alder cycloaddition to a quinone, followed by sequential oxidation steps, is proposed. The final target, rutamycin B, is an antifungal agent for which a lactonization strategy invoking conjugate carboxylate addition, followed by spiroketalization, is proposed. A plan for construction of the nine stereogenic centers in the C(1)-C(16) segment of rutamycin is suggested that begins with cycloaddition of an oxoallyl cation to a chiral furan.